The vesicular monoamine transporter (VMAT) is a transport protein integrated into the membrane of synaptic vesicles of presynaptic neurons. It acts to transport monoamine neurotransmitters—such as dopamine, serotonin, norepinephrine, epinephrine, and histamine—into the vesicles, which release the neurotransmitters into synapses as chemical messages to postsynaptic neurons. Pharmaceutical drugs that target VMATs have possible applications for many conditions. These applications include hypertension, drug addiction, psychiatric disorders, Parkinson's disease, and other neurological disorders. There are two types of VMATs expressed in humans: VMAT1 and VMAT2.
The vesicular monoamine transporter 2 (VMAT2) also known as solute carrier family 18 member 2 (SLC18A2) is a protein that in humans is encoded by the SLC18A2 gene. VMAT2 transports monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine—from cellular cytosol into synaptic vesicles. If VMAT2 function is inhibited or compromised, such neurotransmitters cannot be released via normal transport (exocytosis, action potential) into the synapse.
The compound Valbenazine is a highly selective, small-molecule vesicular monoamine transporter 2 (VMAT2) inhibitor being developed by Neurocrine Biosciences for the treatment of a variety of central nervous system disorders, such as involuntary hyperkinetic movement disorders including drug-induced tardive dyskinesia and Tourette's syndrome. It is known that Valbenazine regulates levels of dopamine release during nerve communication, but has minimal impact on other monoamines, which may help to reduce the likelihood of “off-target” side effects. Valbenazine is in phase III development for drug-induced dyskinesia in patients with schizophrenia or schizoaffective disorder. Phase II development is underway for the treatment of adult patients with Tourette's syndrome. Furthermore, preclinical studies in models of schizophrenia is underway. Valbenazine may be useful in other disorders such as Huntington's disease and tardive dystonia.
Valbenazine has the chemical name (S)-2-Amino-3-methyl-butyric acid, (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolizin-2-yl ester. It is also known as NBI-98854 and has the following chemical structure according to Formula I:

WO 2008/058261 A1 discloses the production of valbenazine as free compound (compound 2-1 in Example 2). The document further discloses the administration of single oral doses of valbenazine in 10% PEG in 0.25% methylcellulose in milli Q water to rats for a pharmacokinetic evaluation (Example 6). The document discloses a composition formulated as liquid solution which is often inconvenient or even unacceptable for use in a pharmaceutical product. There is thus a need for useful alternatives to the liquid compositions disclosed in WO 2008/058261 A1.
Nowadays, one of the most common dosage forms produced by pharmaceutical industries and preferred by the majority of patients are oral dosage forms (such as tablets or capsules). They are more preferable than any other dosage form as they are taken orally by patients, which is a convenient and safe way of drug administration and are more stable compared to liquids (physical and chemical stability). Different types of oral dosage forms require a different formulation in order to be produced as each category has different properties, and alterations may be needed in the choice of excipients and choice of the solid form of the active ingredient each time. That means that every oral dosage form is a different situation.
WO 2015/171802 A1 discloses oral administration of valbenazine to patients (Example 2). According to page 16, lines 16-17 of the document, valbenazine is preferably used in form of its dihydrochloride or ditosylate salt. Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient often possess different properties. There is still a need for useful alternatives to the dihydrochloride and ditosylate salt disclosed in WO 2015/171802 A1.
New salts, solid state forms and solvates of an active pharmaceutical ingredient may have desirable or even improved processing properties compared to known salts, solid state forms and solvates. New salts, solid state forms and solvates of an active pharmaceutical ingredient may be easy to handle during the production or formulation process, suited for storage, allow purification or allow conversion to even further salts or polymorphic forms. Such properties of different salts and solid state forms and solvates in turn can allow desirable pharmaceutical formulations, for example, formulations with a desirable dissolution profile, or with desirable stability and shelf-life. Compared to known salts, solid state forms and solvates, new salts, solid state forms and solvates of an active pharmaceutical ingredient may also show improved properties during production or formulation process, or in the formulation.
In particular, there is still a need for a further solid state form of the active pharmaceutical ingredient valbenazine which form has one or more of the above-indicated desirable or improved properties. There is also a need for a further pharmaceutical composition containing such a solid state form of the active pharmaceutical ingredient valbenazine which composition has one or more of the above-indicated desirable properties.